ATP- and Adenosine-Mediated Signaling in the Central Nervous System: Adenosine Receptor Activation by ATP Through Rapid and Localized Generation of Adenosine by Ecto-nucleotidases

Abstract

Abstract. Extracellular ATP is now recognized as a neurotransmitter or neuromodilator in the nervous system, producing diverse physiological effects by activating multiple P2 receptors. Although P2-receptor signaling is terminated by hydrolysis of ATP by the ecto-nucleotidase cascade, such a metabolic step leads to adenosine generation, thereby initiating adenosine (P1)-receptor activation. Because most cells and tissues co-express P1 and P2 receptors, ecto-nucleotidase on target tissues, especially enzymes catalyzing adenosine formation, are determinants of the cellular response to ATP. Ecto-5'-nucleotidase (E-5'-NT) has been considered to play a principal role in conversion of AMP to adenosine. In addition to E-5'-NT, we have recently demonstrated that ecto-alkaline phosphatase is also involved in ATP-induced P1-receptor activation through a rapid and localized adenosine production on the membrane surface. In this minireview, we describe the pharmacological profile of ecto-nucleotidase-dependent P1-receptor activation by ATP and molecular bases of preferential delivery of metabolically generated adenosine to P1 receptors. Several lines of evidence suggest that the close association between ecto-nucleotidases and P1 receptors may constitute a functional receptor for extracellular ATP, and some physiological responses to ATP would occur through this mechanism.

Engrailed homeoprotein recruits the adenosine A1 receptor to potentiate ephrin A5 function in retinal growth cones

“…A possible explanation for the latter result is that ATP degradation products, rather than ATP itself, participate in the Engrailed enhancing activity. We thus blocked ATP degradation with either ,-methylene-ATP or ,-methylene-ATP, two ectonucleotidase inhibitors (Matsuoka and Ohkubo, 2004). These treatments abolished Engrailed synergistic activity (Fig.…”

Selective Up-regulation of P2X4-Receptor Gene Expression by Interferon-γ in Vascular Endothelial Cells

“…These effects were induced by alteration of gene transcription via the STAT1-mediated signaling pathway. Although we focused in this study on P2-receptor-signaling system, IFN-γ also affects the P1-receptor-signaling system, which is initiated by ATP through ecto-nucleotidasemediated adenosine formation (37,38). Indeed, IFN-γ was reported to up-regulate the adenosine generating enzyme ecto-5'-nucleotidase (39).…”

Purinergic Signalling in the CNS

“…Although adenosine, following ectoenzymatic breakdown of ATP, is the predominant, presynaptic modulator of transmitter release in the CNS (see [29]), ATP itself can also act presynaptically [48]. A strong case is made for coordinated purinergic regulatory systems in the CNS controlling local network behaviours by regulating the balance between the effects of ATP, adenosine and ectonucleotidases on synaptic transmission [49,50].…”